"Pulmonary epithelium is devided into three histopathologically distinct compartments: bronchi, bronchioli, and alveoli. Our long term goal is to characterize the morphological changes, aberrant cellular differentiation and genetic damage associated with progression of premalignant changes in each compartment." "A.Morphologic atypias. Using resection specimens from lung cancer patients and patients without lung cancer we have shown that morphologic changes may proceed independently during field cancerization. In the alveolar compartment, where most of the adenocarcinomas originate, candidate early lesions included bronchiolization of alveoli (BOA). We showed that up to 12% of non-small cell lung cancer resection specimens contain BOA which display a range of morphologic atypias, aberrant cellular differentiation and genetic changes which we characterized." "B. Peripheral airway cell (PAC) and neuroendocrine (NE) differentiation We have shown that field cancerization in human lung is also associated with alterations in the expression patterns of PAC and NE markers. We have now defined an animal model in which the pulmonary changes parallel those seen in man. In response to carcinogen, there is a three-fold decrease in the expression of Clara cell specific protein (CC10), a PAC marker of progenitor cells in non-neoplastic and neoplastic airway epithelium. This is followed by NE cell hyperplasia and tumor formation later on. To analyze the changes in detail, we are using computer- assisted interactive morphometry with a novel application we have developed. In addition, we were able to demonstrate that a neural transcription factor from Drosophila, achaete-schute homolog-1 is expressed in human lung and is essential for NE differentiation in neoplastic and non-neoplastic lung. This provides a unique tool to address the aberrant NE differentiation in the bronchiolar compartment during carcinogenesis." "C. Oncogenes and tumor suppressor genes We combined PCR analyses with microdissection, and noted frequent chromosome 3p abnormalities throughout the pulmonary epithelium including BOAs and other alveolar metaplasias suggesting that these changes occur early in carcinogenesis. A novel approach using in situ PCR reaction was developed for topographic genotyping of p53 and K-ras alterations of which appear to be later events. We will now use the recently developed laser capture microdissection (LCM) to enhance our ability for more detailed topographic genotyping of the lesions in a variety of patient material." The significance of the project is that the results will provide a rational basis for early detection and intervention in human lung cancer by identifying specific markers as well as distinct models for multistep epithelial carcinogenesis.